Why do we age? And why do our cells sometimes “go wrong”? These are questions that humans have been pondering for centuries. Now, scientists are discovering the secrets of cell-level processes via epigenetics.
Changes to gene expression in cells are not always caused by alterations to the DNA sequence – and epigenetics is the study of these changes. DNA methylation is one of the epigenetic changes that is of particular interest to disease research. When methylation goes wrong, it can lead to the development of conditions including cardiovascular, neurological, metabolic, endocrine, and immunological disorders, as well as cancer.
However, little is understood of the mechanisms of DNA methylation – a situation that prompted researchers at Vilnius University, Lithuania, to develop a new method to study real-time changes in methylation in living cells.
Their research, published in the Journal of the American Chemical Society, introduces the method, which could help deepen our understanding of cell development, cancer pathology, and the aging process. Lead author, Liepa Gasiulė, told us about the research and its significance.
What is DNA methylation and what do we know about the way it affects biological processes?
DNA methylation is a universal and fundamental process that occurs in every human cell, whereby a DNA molecule is modified by the addition of a methyl group to it. This process usually results in the “switching off” of gene expression in cells, which means that important biological processes are altered.
How is DNA methylation associated with methionine, and why is that association important?
The amino acid methionine is synthesized in cells to make the essential molecule, AdoMet, from which the methyl group is transferred to DNA – the methylation process. If there is no methionine, then there is no AdoMet formation, and no DNA methylation.
Studies have shown that a low-methionine diet can extend the lifespan of mice, suggesting that the amount of this amino acid is directly related to aging processes. It has also been established that cancer cells are highly dependent on methionine obtained from their environment.
What is your group's new method for studying epigenetic changes in cells?
We developed the method by genetically modifying mouse embryonic cells. After feeding the modified cells with a non-toxic, chemically modified version of methionine, we enabled the cells themselves to make a modified synthetic AdoMet molecule. From such AdoMet, the DNA was tagged with a molecule longer than the methyl group – a sort of “tail” with which we could pull out the modification and identify where the methylation had been altered.
Most importantly, our new method allows us to track DNA methylation in living cells both in the presence of methionine and in its starvation. This allows us to identify how this process varies according to the availability of methionine in the environment.
What were the challenges in developing this method?
The main challenge was to introduce specific targeted mutations into the genome of mouse cells using precise CRISPR/Cas9 technology, while keeping the cells viable and without altering their natural properties.
Figure Credit: American Chemical Society https://creativecommons.org/licenses/by/4.0/
Why is it important to be able to monitor methylation changes in living cells?
Our knowledge of the mechanisms underlying different pathophysiologies is expanded by the discovery of methylation. In addition to helping us understand how and why diseases arise, this also helps us uncover biomarkers for diseases, which speeds up disease detection and provides answers for more efficient disorder treatment.
How might this method help to progress our understanding of diseases?
The method was developed using mouse embryonic cells that can differentiate into other cell types – enabling us to study changes in the development of an organism.
We also know that cancer cells are heavily dependent on externally available methionine. Preclinical studies in mice show that a low-methionine diet enhances the efficacy of chemotherapeutic drugs and radiotherapy and reduces metastasis. Clinical trials of a low-methionine diet for cancer treatment are already underway. However, the mechanisms of what happens to cells on a methionine-restricted diet are still unclear. Hence, cancer cell research could be another application of our method.
How might it help us understand the aging process?
As we age, the coherence of methylation changes – many genes lose their methylation modifications, but some are, on the contrary, strongly methylated. Of course, this may also depend on the amount of methionine in the diet – a methionine-restricted diet can extend the lifespan of mice, rats, and fruit flies.
It is important to note that short-term methionine restriction can reduce inflammatory processes in the body, as well as reducing the development of heart disease and obesity, and improving gut and brain function. Conversely, excessive methionine intake promotes the development of disease. Therefore, the application of this approach in aging models would lead to a better understanding of aging mechanisms.
What is next for this research?
We will continue to deepen and broaden our research in the fields of cancer and aging, and we believe that our research will contribute to society.
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